Chemosensitization of Pancreatic Cancer Cells by Curcumin and Vitamin D Receptor

姜黄素和维生素 D 受体对胰腺癌细胞的化疗增敏作用

• 批准号: 8636411
• 负责人: Timothy Yen
• 金额: $ 22.6万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8636411
• 关键词: Address; Adenocarcinoma; Agonist; Alleles; Beryllium; Biological Factors; Calcium; Cancer Etiology; Cancer Patient; Cancer cell line; Cell Line; Cell Survival; Cells; Cessation of life; Chemosensitization; Clinical; Collection; Combined Modality Therapy; Complex; Consensus; Curcumin; Cytotoxic agent; DNA Damage; DNA damage checkpoint; Data; Diagnosis; Diagnostic; Disease; Dose; Doxorubicin; Early Diagnosis; Etoposide; Exhibits; Fluorouracil; Genes; Genetic Transcription; Homeostasis; In Vitro; Leucovorin; Libraries; Life Expectancy; Ligands; Link; Malignant neoplasm of pancreas; Mediating; Methods; Mitotic; Molecular; Nuclear Hormone Receptors; Operative Surgical Procedures; Pancreas; Pancreatic Adenocarcinoma; Pathway interactions; Patients; Pharmaceutical Preparations; Phase III Clinical Trials; Physiologic calcification; Play; Promoter Regions; Property; Proteins; RNA Interference; Radiation; Regimen; Regulation; Relative (related person); Resistance; Role; Site; Small Interfering RNA; Staging; Testing; Time; Toxic effect; Transactivation; Treatment outcome; Tumeric; Tumor Cell Line; United States; Vitamin D; Vitamin D Analog; Vitamin D3 Receptor; base; cancer cell; cancer therapy; cell killing; chemosensitizing agent; chemotherapy; clinical efficacy; gemcitabine; genome-wide; improved; inhibitor/antagonist; irinotecan; killings; meetings; mutant; nucleoside analog; outcome forecast; oxaliplatin; pancreatic cancer cells; pancreatic neoplasm; promoter; public health relevance; research study; response; sobriety; statistics; success; treatment strategy; tumor

DESCRIPTION (provided by applicant): Pancreatic cancer (adenocarcinoma) is the fourth leading cause of cancer deaths in the United States and carries the worst prognosis, with median life expectancy of less than a year. As the disease is diagnosed at a late stage, treatment options are limited. Surgery only modestly improves life expectancy. Pancreatic adenocarcinomas are highly refractile to conventional chemotherapies. Relative to radiation and paclitaxal, gemcitabine is recognized to be the more efficacious drug. The sobering statistic, however, is that gemcitabine only extends patient survival by several months over other therapies. The molecular basis for chemoresistance is likely to be highly complex, as combination therapies with gemcitabine have met with limited success. There is an urgent need to identify methods to enhance sensitivity of pancreatic cancer cells to chemotherapy. In preliminary experiments, we conducted a genome-wide siRNA screen to identify genes responsible for gemcitabine sensitivity. We identified a small collection of genes that include the vitamin D receptor (VDR) and various associated interacting and downstream genes. We have validated VDR to be an important determinant of gemcitabine sensitivity in vitro. Using an independent set of VDR siRNAs, gemcitabine sensitization was achieved in two cell lines (Panc1 and BXPC3) as determined by clonogenic survival. VDR is a nuclear hormone receptor that is best known for its ability to regulate genes important for calcium homeostasis and mineralization of bone. However, the activities of VDR are vast and complex as its also known for its anti-proliferative properties and is being tested in combination with cytotoxic agents for cancer treatment. We have found that VDR is required for the formation of DNA damaged foci in cells treated with DNA damaging agents. Chemosensitization of cells lacking VDR may therefore be due to disruption of DNA damage response that promote cell survival. This proposal seeks to extend the recent finding that the natural compound curcumin is a ligand for VDR. The use of curcumin as a chemosensitizer is well documented but its mode of action remains obscure. These observations combined with our preliminary data leads us to propose that curcumin acts via VDR to enhance chemosensitzation of pancreatic cancer cells. Furthermore, as the cytoprotective actions of VDR is known to depend on the context of mutant p53 status, the impact on curcumin induced chemosensitization will also be assessed. Our studies have significant clinical ramifications as a large proportion of pancreatic tumors and cell lines express mutant p53. The status of p53 may dictate whether to treat cancer patients with a vitamin D analog or antagonist and curcumin along with standard chemotherapy.

描述（由申请人提供）：胰腺癌（腺癌）是美国第四大癌症死亡原因，预后最差，平均预期寿命不到一年。由于该病诊断较晚，治疗选择有限。手术只能适度提高预期寿命。胰腺腺癌对常规化疗具有高度的屈光度。相对于放疗和紫杉醇，吉西他滨被认为是更有效的药物。然而，令人警醒的统计数据是，吉西他滨只比其他疗法延长了患者几个月的生存期。化疗耐药的分子基础可能非常复杂，因为与吉西他滨联合治疗的成功率有限。目前迫切需要找到一种方法来提高胰腺癌细胞对化疗的敏感性。在初步实验中，我们进行了全基因组siRNA筛选，以确定与吉西他滨敏感性有关的基因。我们发现了一小部分基因，包括

项目成果

Changing the selectivity of p300 by acetyl-CoA modulation of histone acetylation.

• DOI: 10.1021/cb500726b
• 发表时间: 2015-01-16
• 期刊: ACS CHEMICAL BIOLOGY
• 影响因子: 4
• 作者: Henry, Ryan A.;Kuo, Yin-Ming;Bhattacharjee, Vikram;Yen, Timothy J.;Andrews, Andrew J.
• 通讯作者: Andrews, Andrew J.